tbuckley/cabot-search huggingface dataset:
Adjuvant dendritic cell-based immunotherapy after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in patients with malignant peritoneal mesothelioma: a phase II clinical trial
Authors: Michelle V Dietz, Katrien L A Quintelier, Job P van Kooten, Nadine L de Boer, Madelief Vink, Alexandra R M Brandt-Kerkhof, Cornelis Verhoef, Yvan Saeys, Joachim G J V Aerts, Marcella Willemsen, Sofie Van Gassen, Eva V E Madsen
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Malignant peritoneal mesothelioma (MPM) is an aggressive malignancy with a poor prognosis. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) improves survival outcomes, but recurrence rates remain high. Dendritic cell-based immunotherapy (DCBI) showed promising results in patients with pleural mesothelioma. The primary aim of this trial was to determine feasibility of adjuvant DCBI after CRS-HIPEC. Methods This open-label, single-center, phase II clinical trial, performed in the Erasmus MC Cancer Institute Rotterdam, the Netherlands, included patients with epithelioid MPM. 4–6 weeks before CRS-HIPEC leukapheresis was performed. 8–10 weeks after surgery, DCBI was administered three times biweekly. Feasibility was defined as administration of at least three adjuvant vaccinations in 75% of patients. Comprehensive immune cell profiling was performed on peripheral blood samples prior to and during treatment. Results All patients who received CRS-HIPEC (n=16) were successfully treated with adjuvant DCBI. No severe toxicity related to DCBI was observed. Median progression-free survival (PFS) was 12 months (IQR 5–23) and median overall survival was not reached. DCBI was associated with increased proliferation of circulating natural killer cells and CD4+ T-helper (Th) cells. Co-stimulatory molecules, including ICOS, HLA-DR, and CD28 were upregulated predominantly on memory or proliferating Th-cells and minimally on CD8+ cytotoxic T-lymphocytes (CTLs) after treatment. However, an increase in CD8+ terminally differentiated effector memory (Temra) cells positively correlated with PFS, whereas co-expression of ICOS and Ki67 on CTLs trended towards a positive correlation. Conclusions Adjuvant DCBI after CRS-HIPEC in patients with MPM was feasible and safe, and showed promising survival outcomes. DCBI had an immune modulatory effect on lymphoid cells and induced memory T-cell activation. Moreover, an increase of CD8+ Temra cells was more pronounced in patients with longer PFS. These data provide rationale for future combination treatment strategies. Trial registration number NTR7060; Dutch Trial Register (NTR).
Nivolumab and ipilimumab in combination with radiotherapy in patients with high-risk locally advanced squamous cell carcinoma of the head and neck
Authors: Jennifer M Johnson, Ioannis A Vathiotis, Larry A Harshyne, Ayesha Ali, Voichita Bar Ad, Rita Axelrod, Emily Lorber, Joseph Curry, David M Cognetti, Adam J Luginbuhl, Madalina Tuluc, Scott Keith, Mỹ G Mahoney, Athanassios Argiris
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background The combination of nivolumab and ipilimumab has been approved for the treatment of multiple solid tumors. This was a phase I study investigating definitive radioimmunotherapy (RIT) with nivolumab and ipilimumab for the treatment of locally advanced (LA) squamous cell carcinoma of the head and neck (SCCHN). Methods Patients with newly diagnosed, stage IVA–IVB SCCHN eligible for cisplatin-based chemotherapy received nivolumab (3 mg/kg every 2 weeks for a total of 17 doses) and ipilimumab (1 mg/kg every 6 weeks for a total of 6 doses) starting 2 weeks prior to radiotherapy. The primary endpoint was safety of definitive RIT. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Exploratory endpoints included the association of baseline programmed death-ligand 1 (PD-L1) expression as well as on-treatment changes in immune bias with treatment outcomes. Results Twenty-four patients were enrolled. With a median follow-up of 36.1 months, grade 3 or higher treatment-related adverse events were reported in 21 individuals (88%); 5 individuals developed in-field soft tissue ulceration during consolidation immunotherapy, resulting in one fatality. The 3-year PFS and OS rates were 74% (95% CI 58% to 94%) and 96% (95% CI 88% to 100%), respectively. PD-L1 combined positive score (CPS) did not correlate with death or disease progression. Decreases in extracellular vesicle PD-L1 within the concurrent RIT phase were associated with prolonged PFS (p=0.006). Also, interval decreases in circulating interleukin (IL)4, IL9, IL12, and IL17a during concurrent RIT were associated with subsequent ulceration. Conclusions Definitive RIT with nivolumab and ipilimumab has sufficient clinical activity to support further development. Early changes in circulating biomarkers appear able to predict treatment outcomes as well as ensuing in-field soft tissue ulceration. Trial registration number NCT03162731 .
Circulating immune cell dynamics as outcome predictors for immunotherapy in non-small cell lung cancer
Authors: Alvaro Marcos Rubio, Celine Everaert, Eufra Van Damme, Katleen De Preter, Karim Vermaelen
Journal: Journal for ImmunoTherapy of Cancer (2023)

The use of immune checkpoint inhibitors (ICIs) continues to transform the therapeutic landscape of non-small cell lung cancer (NSCLC), with these drugs now being evaluated at every stage of the disease. In contrast to these advances, little progress has been made with respect to reliable predictive biomarkers that can inform clinicians on therapeutic efficacy. All current biomarkers for outcome prediction, including PD-L1, tumor mutational burden or complex immune gene expression signatures, require access to tumor tissue. Besides the invasive nature of the sampling procedure, other disadvantages of tumor tissue biopsies are the inability to capture the complete spatial heterogeneity of the tumor and the difficulty to perform longitudinal follow-up on treatment. A concept emerges in which systemic immune events developing at a distance from the tumor reflect local response or resistance to immunotherapy. The importance of this cancer 'macroenvironment', which can be deciphered by comprehensive analysis of peripheral blood immune cell subsets, has been demonstrated in several cutting-edge preclinical reports, and is corroborated by intriguing data emerging from ICI-treated patients. In this review, we will provide the biological rationale underlying the potential of blood immune cell-based biomarkers in guiding treatment decision in immunotherapy-eligible NSCLC patients. Finally, we will describe new techniques that will facilitate the discovery of more immune cell subpopulations with potential to become predictive biomarkers, and reflect on ways and the remaining challenges to bring this type of analysis to the routine clinical care in the near future.
Prospective, randomized, double-blind phase 2B trial of the TLPO and TLPLDC vaccines to prevent recurrence of resected stage III/IV melanoma: a prespecified 36-month analysis
Authors: Elizabeth Lee Carpenter, Spencer Van Decar, Alexandra M Adams, Anne E O’Shea, Patrick McCarthy, Robert Connor Chick, Guy Travis Clifton, Timothy Vreeland, Franklin A Valdera, Ankur Tiwari, Diane Hale, Phillip Kemp Bohan, Annelies Hickerson, Todd Smolinsky, Katryna Thomas, Jessica Cindass, John Hyngstrom, Adam C Berger, James Jakub, Jeffrey J Sussman, Montaser F Shaheen, Xianzhong Yu, Thomas E Wagner, Mark Faries, George E Peoples
Journal: Journal for ImmunoTherapy of Cancer (2023)

The tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine is made by ex vivo priming matured autologous dendritic cells (DCs) with yeast cell wall particles (YCWPs) loaded with autologous tumor lysate (TL). The tumor lysate, particle only (TLPO) vaccine uses autologous TL-loaded YCWPs coated with silicate for in vivo DC loading. Here we report the 36-month prespecified analyses of this prospective, randomized, double-blind trial investigating the ability of the TLPO and TLPLDC (±granulocyte-colony stimulating factor (G-CSF)) vaccines to prevent melanoma recurrence in high-risk patients.Patients with clinically disease-free stage III/IV melanoma were randomized 2:1 initially to TLPLDC versus placebo (n=124) and subsequently TLPO versus TLPLDC (n=63). All patients were randomized and blinded; however, the placebo control arm was replaced in the second randomization scheme with another novel vaccine; some analyses in this paper therefore reflect a combination of the two randomization schemes. Patients receiving the TLPLDC vaccine were further divided by their method of DC harvest (with or without G-CSF pretreatment); this was not randomized. The use of standard of care checkpoint inhibitors was not stratified between groups. Safety was assessed and Kaplan-Meier and log-rank analyses compared disease-free (DFS) and overall survival (OS).After combining the two randomization processes, a total of 187 patients were allocated between treatment arms: placebo (n=41), TLPLDC (n=103), or TLPO (n=43). The allocation among arms created by the addition of patients from the two separate randomization schemes does not reflect concurrent randomization among all treatment arms. TLPLDC was further divided by use of G-CSF in DC harvest: no G-CSF (TLPLDC) (n=47) and with G-CSF (TLPLDC+G) (n=56). Median follow-up was 35.8 months. Only two patients experienced a related adverse event ≥grade 3, one each in the TLPLDC+G and placebo arms. DFS was 27.2% (placebo), 55.4% (TLPLDC), 22.9% (TLPLDC+G), and 60.9% (TLPO) (p<0.001). OS was 62.5% (placebo), 93.6% (TLPLDC), 57.7% (TLPLDC+G), and 94.6% (TLPO) (p=0.002).The TLPO and TLPLDC (without G-CSF) vaccines were associated with improved DFS and OS in this clinical trial. Given production and manufacturing advantages, the efficacy of the TLPO vaccine will be confirmed in a phase 3 trial.NCT02301611.
Chronic immune-related adverse events in patients with cancer receiving immune checkpoint inhibitors: a systematic review
Authors: Carly C Barron, Isabella Stefanova, Yevin Cha, Karam Elsolh, Arman Zereshkian, Nessma Gaafour, Elaine McWhirter
Journal: Journal for ImmunoTherapy of Cancer (2023)

Immune-related adverse events (irAEs) are toxicities resulting from use of immune checkpoint inhibitors (ICIs). These side effects persist in some patients despite withholding therapy and using immunosuppressive and immune-modulating agents. Little is known about chronic irAEs and they are felt to be rare. We performed a systematic review to characterize non-endocrine chronic irAEs reported in the literature and describe their management. Ovid MEDLINE and Embase databases were searched for reports of adult patients with solid cancers treated with ICIs who experienced chronic (&gt;12 weeks) non-endocrine irAEs. Patient, treatment and toxicity data were collected. Of 6843 articles identified, 229 studies including 323 patients met our inclusion criteria. The median age was 65 (IQR 56–72) and 58% were male. Most patients (75%) had metastatic disease and the primary cancer site was melanoma in 43% and non-small cell lung cancer in 31% of patients. The most common ICIs delivered were pembrolizumab (24%) and nivolumab (37%). The chronic irAEs experienced were rheumatological in 20% of patients, followed by neurological in 19%, gastrointestinal in 16% and dermatological in 14%. The irAE persisted for a median (range) of 180 (84–2370) days and 30% of patients had ongoing symptoms or treatment. More than half (52%) of patients had chronic irAEs that persisted for &gt;6 months. The ICI was permanently discontinued in 60% of patients and 76% required oral and/or intravenous steroids. This is the first systematic review to assess and report on moderate/severe chronic non-endocrine irAEs after treatment with ICI in the literature. These toxicities persisted for months-years and the majority required discontinuation of therapy and initiation of immunosuppression. Further research is needed to better understand chronic irAEs, which hold potential substantial clinical significance considering the expanded use of ICIs and their integration into the (neo)adjuvant settings.
Multiple TMA-aided CRISPR/Cas13a platform for highly sensitive detection of IL-15 to predict immunotherapeutic response in nasopharyngeal carcinoma
Authors: Ya-Xian Wu, Shan Xing, Yu Wang, Bo-Yu Tian, Meng Wu, Xue-Ping Wang, Qi Huang, Xia He, Shu-Lin Chen, Xiao-Hui Li, Mu-Sheng Zeng, Wan-Li Liu
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Immune checkpoint inhibitors (ICIs)-based treatments have been recommended as the first line for refractory recurrent and/or metastatic nasopharyngeal carcinoma (NPC) patients, yet responses vary, and predictive biomarkers are urgently needed. We selected serum interleukin-15 (sIL-15) out of four interleukins as a candidate biomarker, while most patients’ sIL-15 levels were too low to be detected by conventional methods, so it was necessary to construct a highly sensitive method to detect sIL-15 in order to select NPC patients who would benefit most or least from ICIs. Methods Combining a primer exchange reaction (PER), transcription-mediated amplification (TMA), and a immuno-PER-TMA-CRISPR/Cas13a system, we developed a novel multiple signal amplification platform with a detection limit of 32 fg/mL, making it 153-fold more sensitive than ELISA. Results This platform demonstrated high specificity, repeatability, and versatility. When applied to two independent cohorts of 130 NPC sera, the predictive value of sIL-15 was accurate in both cohorts (area under the curve: training, 0.882; validation, 0.898). Additionally, lower sIL-15 levels were correlated with poorer progression-free survival (training, HR: 0.080, p&lt;0.0001; validation, HR: 0.053, p&lt;0.0001). Conclusion This work proposes a simple and sensitive approach for sIL-15 detection to provide insights for personalized immunotherapy of NPC patients.
Table of Contents
Authors: Shaul Massry, Joel Kopple, Miroslaw Smogorzewski, Garabed Eknoyan, Vesna Garovic, Giorgina Piccoli, Sami Alasfar, Wasim Zakaria, Haj Khaled, Abdul Nasan, Fahd Zanabli, Ahmad Al-Saghir, Valerie Rifai, Lina Luyckx, Saleh Murad, Akram Kaysi, Mohamed Al-Makki, Opeyemi Olabisi, Heidi Karttunen, Michael Ross, Nicholas Steers, Jonathan Barasch, Dawn Caster, David Powell, Alexandre Benmerah, Luis Briseño-Roa, Jean-Philippe Annereau, Sophie Saunier, Jonathan Barratt, Richard Lafayette, Hong Zhang, Vladimir Tesar, Brad Rovin, James Tumlin, Heather Reich, Jürgen Floege, Carl May, Musleeha Chesor, Sarah Hunter, Bryony Hayes, Rachel Barr, Tim Roberts, Fern Barrington, Louise Farmer, Lan Ni, Maisie Jackson, Heidi Snethen, Nadia Tavakolidakhrabadi, Max Goldstone, Rodney Gilbert, Matt Beesley, Rachel Lennon, Rebecca Foster, Richard Coward, Gavin Welsh, Moin Saleem Open, Adrian Goldspink, Jessica Schmitz, Olena Babyak, Nicolas Brauns, Julia Milleck, Anne Breloh, Susanne Fleig, Katarzyna Jobin, Lisa Schwarz, Hermann Haller, Florian Wagenlehner, Jan Bräsen, Christian Kurts, Sibylle Von Vietinghoff, Antonia Sanad, Fatimunnisa Qadri, Elena Popova, Felipe André, Timm Rodrigues, Susanna Heinbokel, Angela Quach, Sebastian Schulz, Reinhold Bachmann, Natalia Kreutz, Michael Alenina
Journal: Kidney International (2023)
LION: Taming RNA vaccine inflammation
Authors: John S. Tregoning
Journal: Molecular Therapy (2023)

The COVID-19 pandemic demonstrated the utility of RNA vaccines as a flexible platform that can be rapidly deployed to control emerging infections. RNA vaccines have huge potential for use against a wide range of pathogens. One of the challenges with their broader rollout is systemic inflammation and adverse side effects. However, certain types of inflammation are necessary for the induction of an adaptive immune response to an RNA vaccine. 1 Tregoning J.S. Stirling D.C. Wang Z. Flight K.E. Brown J.C. Blakney A.K. McKay P.F. Cunliffe R.F. Murugaiah V. Fox C.B. et al. Formulation, inflammation, and RNA sensing impact the immunogenicity of self-amplifying RNA vaccines. Mol. Ther. Nucleic Acids. 2023; 31: 29-42https://doi.org/10.1016/j.omtn.2022.11.024 Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar Approaches that focus inflammation where it is needed and reduce systemic responses could be extremely beneficial. In the August issue of Molecular Therapy, Kimura et al. investigated how RNA vaccine formulations can alter this inflammation profile. 2 Kimura T. Leal J.M. Simpson A. Warner N.L. Berube B.J. Archer J.F. Park S. Kurtz R. Hinkley T. Nicholes K. et al. A localizing nanocarrier formulation enables multi-target immune responses to multivalent replicating RNA with limited systemic inflammation. Mol. Ther. 2023; 31: 2360-2375https://doi.org/10.1016/j.ymthe.2023.06.017 Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar
CD8+ T cells maintain killing of MHC-I-negative tumor cells through the NKG2D–NKG2DL axis
Authors: Emily C Lerner, Karolina I Woroniecka, Vincent M D'Anniballe, Daniel S Wilkinson, Aditya A Mohan, Selena J Lorrey, Jessica Waibl-Polania, Lucas P Wachsmuth, Alexandra M Miggelbrink, Joshua D Jackson, Xiuyu Cui, Jude A Raj, William H Tomaszewski, Sarah L Cook, John H Sampson, Anoop P Patel, Mustafa Khasraw, Michael D Gunn, Peter E Fecci
Journal: Nature Cancer (2023)

The accepted paradigm for both cellular and anti-tumor immunity relies upon tumor cell killing by CD8
Next generation 3D-printed intravaginal ring for prevention of HIV and unintended pregnancy
Authors: Isabella C. Young, Priya Srinivasan, Roopali Shrivastava, Rima Janusziewicz, Allison Thorson, Mackenzie L. Cottrell, Rani S. Sellers, Craig Sykes, Amanda Schauer, Dawn Little, Kristen Kelley, Angela D.M. Kashuba, David Katz, Richard B. Pyles, J. Gerardo García-Lerma, Kathleen L. Vincent, James Smith, S. Rahima Benhabbour
Journal: Biomaterials (2023)
WNTinib is a multi-kinase inhibitor with specificity against β-catenin mutant hepatocellular carcinoma
Authors: Alex Rialdi, Mary Duffy, Alex P. Scopton, Frank Fonseca, Julia Nanyi Zhao, Megan Schwarz, Pedro Molina-Sanchez, Slim Mzoughi, Elisa Arceci, Jordi Abril-Fornaguera, Austin Meadows, Marina Ruiz de Galarreta, Denis Torre, Kyna Reyes, Yan Ting Lim, Felix Rosemann, Zaigham M. Khan, Kevin Mohammed, Xuedi Wang, Xufen Yu, Manikandan Lakshmanan, Ravisankar Rajarethinam, Soo Yong Tan, Jian Jin, Augusto Villanueva, Eleftherios Michailidis, Ype P. De Jong, Charles M. Rice, Ivan Marazzi, Dan Hasson, Josep M. Llovet, Radoslaw M. Sobota, Amaia Lujambio, Ernesto Guccione, Arvin C. Dar
Journal: Nature Cancer (2023)
Somatic mutations in facial skin from countries of contrasting skin cancer risk
Authors: Charlotte King, Joanna C Fowler, Irina Abnizova, Roshan K Sood, Michael W J Hall, Ildikó Szeverényi, Muly Tham, Jingxiang Huang, Stephanie Ming Young, Benjamin A Hall, E Birgitte Lane, Philip H Jones
Journal: Nature Genetics (2023)

The incidence of keratinocyte cancer (basal cell and squamous cell carcinomas of the skin) is 17-fold lower in Singapore than the UK1-3, despite Singapore receiving 2-3 times more ultraviolet (UV) radiation4,5. Aging skin contains somatic mutant clones from which such cancers develop6,7. We hypothesized that differences in keratinocyte cancer incidence may be reflected in the normal skin mutational landscape. Here we show that, compared to Singapore, aging facial skin from populations in the UK has a fourfold greater mutational burden, a predominant UV mutational signature, increased copy number aberrations and increased mutant TP53 selection. These features are shared by keratinocyte cancers from high-incidence and low-incidence populations8-13. In Singaporean skin, most mutations result from cell-intrinsic processes; mutant NOTCH1 and NOTCH2 are more strongly selected than in the UK. Aging skin in a high-incidence country has multiple features convergent with cancer that are not found in a low-risk country. These differences may reflect germline variation in UV-protective genes.
Defining a research agenda for environmental wastewater surveillance of pathogens
Authors: Alexander G. Shaw, Catherine Troman, Joyce Odeke Akello, Kathleen M. O’Reilly, Jillian Gauld, Stephanie Grow, Nicholas Grassly, Duncan Steele, David Blazes, Supriya Kumar, Farah Naz Qamar, Imran Nisar, Christian Walder, Amrita Sekhar, Kimberly Porter, Kirsten Vannice, Kayla Laserson, Lungi Okoko, Michelle Morrison, Samantha Dolan, Simon Harris, Steve Kroiss, Vincent Seaman, Mariana Matus, Angela Chaudhuri, Taslimareif Saiyed, Ben Lepene, Robbie Barbero, Cristina M. Tato, Katrina Kalantar, Dilip Abraham, Gagandeep Kang, Jacob John, Venkata Raghava Mohan, Karen Menge, John Dennehy, Gavin J. D. Smith, Ana Burgos Gutierrez, Damla Bilgin, Michael Oberholzer, Nitzan Soffer, Vanessa Moeder, Christopher Uzzell, Isobel Blake, Erik Karlsson, Mahbubur Rahman, Tahmina Shirin, Raphaël M. Zellweger, Amanda Debes, Michael Owusu, Sampson Twumasi-Ankrah, Yaw Adu-Sarkodie, Jonathan Rigby, Kayla Barnes, Nicholas Feasey, Hamilton Bennett, Amanda Handley, Julie Bines, Kerrigan McCarthy, Mukhlid Yousif, Lukas von Tobel, Stephane Vouillamoz, Stephen Rudd, David Boyle, Sophie Magnet, Gisela Abbam, Ivan Liachko, Laurette Mhlanga, Nicholas Thomson, Joshua I. Levy, Ben Pyne, Kathie Paul Wilkerson, David Larsen, Farah Ishtiaq, Joshua Trotta, Helen Stembridge, Indah Kartika Murni, Vicka Oktaria, Marietjie Venter, Andy Tatem, Mami Taniuchi, John Scott Meschke, Bradley J. White, Benjamin Yaffe, Josie Golding, Peter Hart, Hamisu Abdullahi, Kate Medlicott, Julia Fitzner
Journal: Nature Medicine (2023)
The serotonin transporter sustains human brown adipose tissue thermogenesis
Authors: Karla J Suchacki, Lynne E Ramage, T'ng Choong Kwok, Alexandra Kelman, Ben T McNeill, Stewart Rodney, Matthew Keegan, Calum Gray, Gillian MacNaught, Dilip Patel, Alison M Fletcher, Joanna P Simpson, Roderick N Carter, Robert K Semple, Natalie Z M Homer, Nicholas M Morton, Edwin J R van Beek, Sonia J Wakelin, Roland H Stimson
Journal: Nature Metabolism (2023)

Abstract Activation of brown adipose tissue (BAT) in humans is a strategy to treat obesity and metabolic disease. Here we show that the serotonin transporter (SERT), encoded by SLC6A4 , prevents serotonin-mediated suppression of human BAT function. RNA sequencing of human primary brown and white adipocytes shows that SLC6A4 is highly expressed in human, but not murine, brown adipocytes and BAT. Serotonin decreases uncoupled respiration and reduces uncoupling protein 1 via the 5-HT 2B receptor. SERT inhibition by the selective serotonin reuptake inhibitor (SSRI) sertraline prevents uptake of extracellular serotonin, thereby potentiating serotonin’s suppressive effect on brown adipocytes. Furthermore, we see that sertraline reduces BAT activation in healthy volunteers, and SSRI-treated patients demonstrate no 18 F-fluorodeoxyglucose uptake by BAT at room temperature, unlike matched controls. Inhibition of BAT thermogenesis may contribute to SSRI-induced weight gain and metabolic dysfunction, and reducing peripheral serotonin action may be an approach to treat obesity and metabolic disease.